Vaccine Manufacturing
Facilities of the Future
Howard L. Levine, Ph.D.
Vaccines Europe
London, England
December 1 – 2, 2010
Challenges in the Production of Vaccines
 Different technology platforms •

•

make it difficult to standardize facility design and equipment
Unique facility and equipment may be necessary for each vaccine or class of vaccine
Many vaccines are typically low volume/high throughput products
≥ 1 million doses per year
Live viral or bacterial vaccines require special fill & finish facilities
 No one facility will fit all products or processes
From Clone to Commercial®
Wide Range of Technologies Available for Vaccine Production
Toxoid
(Bacterial)
Empirical
Live,
attenuated
Virus-like
particle
Killed,
metabolically
active
Recombinant
Vector
Prime/boost combinations
From Clone to Commercial®
Inactivated
Subunit
Purified
DNA
Recombinant
Conjugate
(e.g., proteinpolysaccharide)
Manufacturing Challenges
 Many vaccines contain multiple strains or sub‐units
• Influenza vaccine
 Contains antigens from 3 different strains  Multiple upstream/downstream processes
 Single formulation and fill process
• Prevnar® (Pneumococcal CRM197 Conjugate Vaccines)
 1 carrier protein (CRM197); 7‐15 serotypes of polysaccharides
 Multiple conjugations
 Single formulation and fill process
 Multiple cell lines used for vaccine productioni
• Mammalian cell lines – VERO, MDCK, MRC5, BHK, CHO
• Microbial cell lines – E. coli
From Clone to Commercial®
Current Vaccine Manufacturing Facilities
 Large hard‐piped, stainless steel based facilities with stainless steel bioreactors
 Very expensive to build and validate
• Construction costs ≥$300 Million
• Construction timelines 2‐5 years or more
 Controlled environment, highly classified suites
• Tightly controlled flow of people, materials, and equipment
 Huge utilities for WFI, HVAC, Clean steam, CIP
• Extensive piping, transfer panels,
complex operations
From Clone to Commercial®
Photos courtesy of Lonza Biologics
Diversity of manufacturing facilities in the future
 Complex supply chain and manufacturing
 Scale of upstream processes generally not significant compared to other biopharmaceutical products
 Vaccine manufacturing facilities traditionally require long lead times (3 – 5 years) and large capital investments
 Unpredictability of demand necessitate flexible facilities
 Technology advancements
• Highly purified and characterized products
• Cell culture replacing egg‐based technology
• Introduction of disposable technology
From Clone to Commercial®
A Brief History of Disposable Systems in Biomanufacturing
1970s
Use of flasks,
pipettes, filters,
blood bags
1996
Introduction of
Wave
Bioreactor
1980s
Bags for
media,
harvest,
buffer prep
2004
First 250 L
disposable
bioreactor
1998
First
membrane
adsorbers
2009
First 2,000 L
disposable
bioreactor
 Latest implementation of disposables include bioreactor harvest & clarification, cell concentration, downstream processing, and fill/finish operations
From Clone to Commercial®
Driving Forces for Single-Use Technologies
 Improved return on capital
• Reduced and deferred capital investment
• Increased speed of deployment
• Cost structure shifted to variable costs
 Significant reduction in capital equipment costs (>70%)
 Reduced process equipment complexity
• Process and product flexibility
• Improved process control and portability
 Reduced facility complexity and cost
• Faster construction, commissioning, and launch
• No change‐over cleaning/validation between strains/products
• Significant reduction in facility/equipment validation
From Clone to Commercial®
Disposable Options Across Entire Manufacturing Flowpath
Cell Culture
Recovery/
Downstream
Processing
Disposable Sensors
Media Prep/
Storage
Formulation/
Fill
Buffer Prep/
Storage
All conventional unit operations now have disposable format solutions
From Clone to Commercial®
Current Status of Disposable Systems
 Almost all the unit operations and process components used in 



biomanufacturing can be replaced by disposables
The cost benefit, convenience, and flexibility of moving to disposables are well documented
More and more vendors are developing single use and disposable products
Companies are now moving to disposables for clinical and potentially commercial manufacturing
A completely disposable manufacturing flowpath should be possible in the foreseeable future
From Clone to Commercial®
Process Scale Disposable Bioreactors
Xcellerex
Sartorius
Stedim
Thermo Fisher
(Hyclone)
XDRTM Bioreactor
Biostat® Culti‐bag
Up to 2,000 L
Up to 1,000 L
Single‐use Bioreactor (S.U.B.)
ATMI
NucleoTM Bioreactor
Up to 1,000 L
Up to 2,000 L
GE Healthcare
(Wave)
From Clone to Commercial®
Wave Bioreactor
Up to 1,000 L
Stainless Steel vs. Disposable Bioreactors
 Comparable cell growth and productivity
 No cleaning or sterilization required
 Fast turnaround
 Minimal validation requirements
 Increased flexibility and process portability
From Clone to Commercial®
Production of West Nile Vaccine
100
5.00E+07
4.50E+07
Added
Gl
4.00E+07
3.50E+07
Added Antifoam and Glucose
Cell Density
3.00E+07
Added Antifoam
2.50E+07
2.00E+07
Added Glucose
1.50E+07
1.00E+07
Induce with 0.2 M CuSO4
5.00E+06
Added Antifoam
0.00E+00
0
48
96
144
Time in XDR-200 (h)
 Insect cell production in an XDR bioreactor From Clone to Commercial®
Data courtesy of Xcellerx
80
192
Production of Rabies Vaccine
 Vero cells grown on microcarriers in an ATMI bioreactor
From Clone to Commercial®
Data courtesy of ATMI and sanofi pasteur
Production of Influenza Vaccine
From Clone to Commercial®
Photo and flowchart courtesy of Novavax
Comparison of Disposable Bioreactors for Viral Production
Relative Viral Production
120
100
80
60
40
20
0
Disposable
Bioreactor 1
Disposable
Bioreactor 2
Disposable
Bioreactor 3
Stainless Steel
Bioreactor
 Production of one viral serotype in three different disposable bioreactor systems
From Clone to Commercial®
Ref: Chaudard J‐F, et al, BioPharm Supplement 2010
Vaccine Facility Construction – A Tale of Three Technologies
Traditional egg‐based
Mammalian Cell Culture
Insect Cell Culture
Each fully‐integrated manufacturing facilities designed and estimated by the same US‐based engineering and construction firm in the time period 2004 – 2007
From Clone to Commercial®
Ref: J. Trazzino, BIO2010
Influenza Vaccine Facilities – A Tale of Three Technologies
sanofi pasteur
Novartis
Egg-based Facility
Mammalian Cell Culture Facility
No bioreactors - 600K eggs/day
Stainless steel bioreactors
100M doses/year
50M doses/year
140K square feet
140K square feet
$150M
$600M
Existing site and infrastructure
New site and infrastructure
Novavax
Insect Cell Culture Facility
Single-use bioreactor
75M doses/year
55K square feet
$40M
New site and infrastructure
From Clone to Commercial®
Ref: J. Trazzino, BIO2010
Comparison of Project Duration
Design
Construction
EggBased
Process
Commissioning
Qualification
Validation
Design
Construction
Commissioning
Insect
Cell
Culture
Qualification
Validation
Time Saved
Time, yrs
0
From Clone to Commercial®
1
2
3
Ref: J. Trazzino, BIO2010
4
Disposable Technologies Changing Manufacturing Facilities
 Increased facility utilization by 



reducing change‐over time Reduced fixed piping
Reducing cleaning and validation costs in multi‐
product operations
Improved process portability
Easier to manage and implement process changes
 Increased operational flexibility by minimizing or eliminating multi‐use equipment
From Clone to Commercial®
Photo courtesy of Acceleron Pharma
Next Generation Vaccine Manufacturing Facility
 BPTC and Pharmadule have partnered to develop new modular biomanufacturing facilities
 Standard design incorporates multi‐product capabilities, maximum flexibility, and disposable technologies
 Designed for disposable bioreactors up to 2,000 L
• Potential for multiple bioreactors per module
From Clone to Commercial®
Vaccine Manufacturing Facility Design Criteria and Assumptions
 Designed to meet BSL‐2 requirements
• Inoculum, bulk API filling under LAF protection in Class C
• Class D for cell culture, downstream processing, dish unloading, media and buffer preparation
• Buffer preparation for final steps in Class D, LAF protected
• Media and buffer storage in controlled, non‐classified areas
 Batch duration 8 weeks including change over times
• 4 weeks inoculum train, 2 weeks bioreactor, 1 week purification, 1 week final purification
 1 batch per month with overlap of inoculum preparation and cell culture operations
 12 batches per year multi‐product or 24 batches per year single‐
product
From Clone to Commercial®
Vaccine Manufacturing Modular Facility Layout
 Process building only, connected to a spine with plant utilities
 Separate Mechanical and Process areas
 Segregation of Personnel and Material flow
From Clone to Commercial®
Model Plant – Single-use Floor 1
Supply Corridor
Inoculum
Media & Buffer
Preparation
Wash
Cultivation
Materials Corridor
Staging Area
Final Buffer
Exchange
Bulk API
Filling
Purification
Personnel Corridor
From Clone to Commercial®
Capturing
Cost Comparison – SS Bioreactor vs. Disposable Bioreactor
SS Bioreactor
Disposable Bioreactor
16 months
14 months
Process Area
6372 ft2
6781 ft2
Class C
1109 ft2
667 ft2
Class D
5231 ft2
3315 ft2
0 ft2
2745 ft2
12,153 ft2
13,014 ft2
Piping Length
2854 ft
886 ft
Process Equipment
4.0 m€
3.0 m€
Total Capital Cost
17,3 m€
15 m€
Constrution Time
CNC
Total Area
From Clone to Commercial®
Economics of Stainless Steel vs. Disposables
Start‐up Costs
Operating Costs
Ref: Galliher, 2010; Foulon, et al. 2010
From Clone to Commercial®
Thank you!
BioProcess Technology Consultants, Inc.
12 Gill Street, Suite 5450
Woburn, MA 01801
781.281.2703
hlevine@bioprocessconsultants.com
www.bioprocessconsultants.com
From Clone to Commercial®